The timing of Start is determined primarily by increased synthesis of the Cln3 activator rather than dilution of the Whi5 inhibitor

Litsios, Athanasios; Goswami, Pooja; Terpstra, Hanna M; Coffin, Carleton H.; Vuillemenot, Luc-Alban; Rovetta, Mattia; Ghazal, Ghada; Guerra, Paolo; Buczak, Katarzyna; Schmidt, Alexander; Tollis, Sylvain; Tyers, Mike; Royer, Catherine A.; Milias-Argeitis, Andreas; Heinemann, Matthias

doi:10.1091/mbc.e21-07-0349

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…This dilution may trigger Start once the Whi5 concentration drops below a critical threshold in late G1 phase. However, other quantitative studies have reported that the concentration of Whi5 is independent of cell size and time, i.e., Whi5 continues to be synthesized throughout G1 phase in concert with cell growth (Dorsey et al, 2018;Litsios et al, 2019;Sommer et al, 2021;Litsios et al, 2022). Genetic evidence suggests that constitutive expression of Whi5 at physiological levels does not alter the coupling of size with passage through Start (Barber et al, 2020).…”

Section: Budding and Fission Yeastmentioning

confidence: 98%

“…In contrast to Whi5 dilution, recent single cell measurements suggest that a burst in global protein synthesis in late G1 phase results in the rapid accumulation of the highly unstable G1 cyclin Cln3, which then triggers Start and G1/S transcription by the phosphorylation-dependent inactivation of Whi5 ( Litsios et al, 2019 ; Liu et al, 2015 ; Sommer et al, 2021 ). The Whi5 dilution model remains contentious as the critical underlying quantitative measurements depend heavily on appropriate controls for Whi5 signal loss ( Litsios et al, 2022 ; Schmoller et al, 2022 ). Additional regulators and mechanisms may couple cell size, growth, and Start in budding yeast.…”

Section: Molecular Control Of Cell Size Checkpoints and The Hunt For ...mentioning

confidence: 99%

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What programs the size of animal cells?

Liu

Tan²,

Tyers³

et al. 2022

Front. Cell Dev. Biol.

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The human body is programmed with definite quantities, magnitudes, and proportions. At the microscopic level, such definite sizes manifest in individual cells - different cell types are characterized by distinct cell sizes whereas cells of the same type are highly uniform in size. How do cells in a population maintain uniformity in cell size, and how are changes in target size programmed? A convergence of recent and historical studies suggest - just as a thermostat maintains room temperature - the size of proliferating animal cells is similarly maintained by homeostatic mechanisms. In this review, we first summarize old and new literature on the existence of cell size checkpoints, then discuss additional advances in the study of size homeostasis that involve feedback regulation of cellular growth rate. We further discuss recent progress on the molecules that underlie cell size checkpoints and mechanisms that specify target size setpoints. Lastly, we discuss a less-well explored teleological question: why does cell size matter and what is the functional importance of cell size control?

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Section: Budding and Fission Yeastmentioning

confidence: 98%

Section: Molecular Control Of Cell Size Checkpoints and The Hunt For ...mentioning

confidence: 99%

What programs the size of animal cells?

Liu

Tan²,

Tyers³

et al. 2022

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

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“…Timing of Start at late G1 is regulated by the antagonic interplay between the Cln3 G1 cyclin and the Whi5 inhibitor (De Bruin et al, 2004). Increased synthesis of Cln3 and dilution of Whi5 levels due to cell size increase has been proposed to control has also been proposed to control Start timing and cell size-dependent proliferation (Litsios et al, 2022) (Schmoller et al, 2015b). As cell size increases, Whi5 protein would be progressively diluted and, once it has reached a certain threshold concentration, which should correspond to an optimal division size, cells commit to division (Schmoller et al, 2015b).…”

Section: Whi5 Levels Link Proliferative Heterogeneity To Replicative ...mentioning

confidence: 99%

Cell-cycle regulator Whi5 shapes proliferative heterogeneity in clonal populations

Delgado-Román

Delgado-Ramos

Muñoz-Centeno

2023

Preprint

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Clonal cultures exhibit phenotypic variation in spite of being composed of genetically identical cells under equal environmental conditions. Proliferation rate is one of the characters that have been described to show this heterogeneity, but the mechanisms underlying this phenomenon are still poorly understood. Cell cycle regulation controls proliferative capacity and previous transcriptomic studies revealed that budding yeast microcolonies with low proliferation rates display high levels of the G1-S transition inhibitor Whi5. This regulator, which, in budding yeast, plays a similar role as Retinoblastoma protein in mammalian cells, has been also linked to replicative aging in late steps of mother cells lifespan. In this work, we combined single cell microencapsulation with confocal microscopy to study heterogeneity in clonal cultures. Using this new method, we found that a significant proportion of slow-growing microcolonies are founded by mother cells with a short number of cell cycles. We also found that the reduction in the proliferation capacity of microcolonies founded by young mother cells is related to the expression levels of Whi5, which increases with mother cell age since early stages. Our results establish that stably reduced proliferation is not exclusively linked to old mother cells and indicate that cell age contributes to proliferation heterogeneity by modulating cell cycle regulation.

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“…This model of passive Whi5 dilution requires that Whi5 protein synthesis substantially drops in G1. Recent works have reported size-and time-independent Whi5 protein concentration in G1 cells [10,11,14,18], challenging the dilution model. These results suggest that Whi5 protein is not substantially diluted as cells grow, and therefore that Whi5 synthesis continues in G1.…”

Section: Introductionmentioning

confidence: 99%

“…The current work extends on [18] and aims to address the cell cycle dependence of WHI5 transcription. WHI5 mRNA abundance as a function of cell size has been reported using bulk RNA-sequencing of…”

Section: Introductionmentioning

confidence: 99%

The G1/S repressor WHI5 is expressed at similar levels throughout the cell cycle

Tollis

2022

BMC Res Notes

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Objectives While it is clear that cells need to grow before committing to division at the G1/S transition of the cell cycle, how cells sense their growth rate or size at the molecular level is unknown. It has been proposed that, in budding yeast, the dilution of the Whi5 G1/S transcriptional repressor as cells grow in G1 is the main driver of G1/S commitment. This model implies that Whi5 synthesis is substantially reduced in G1 phase. Recent work has reported that the concentration of Whi5 is size- and time-independent in G1 cells, challenging the dilution model. These results in turn imply that Whi5 must be synthesized in G1 phase, but the cell cycle dependence of WHI5 mRNA expression has not been examined in live cells. Results description To address this question, we monitored single WHI5 mRNA molecules in single live cells using confocal microscopy, and quantified WHI5 mRNA copy number in G1, G1/S, and S/G2/M phase cells. We observed that WHI5 mRNA is found in very similar amount irrespective of cell cycle stage. The constant WHI5 mRNA copy number throughout G1 phase rules out alterations in mRNA abundance as a contributing factor for any putative dilution of Whi5.

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The timing of Start is determined primarily by increased synthesis of the Cln3 activator rather than dilution of the Whi5 inhibitor

Abstract: The timing of Start is determined primarily by increased synthesis of the Cln3 activator rather than dilution of the Whi5 inhibitor

Cited by 11 publications

References 52 publications

What programs the size of animal cells?

What programs the size of animal cells?

Cell-cycle regulator Whi5 shapes proliferative heterogeneity in clonal populations

The G1/S repressor WHI5 is expressed at similar levels throughout the cell cycle

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